An optically active isochroman-2H-chromene conjugate potently suppresses neuronal oxidative injuries associated with the PI3K/Akt and MAPK signaling pathways  

作　　者：Ling-xue Tao Sha-sha Ji Dóra Szalóki Tibor Kovács Attila Mándi Sándor Antus Xun Ding Tibor Kurtán Hai-yan Zhang 

机构地区：[1]CAS Key Laboratory of Receptor Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [2]Department of Organic Chemistry,University of Debrecen,Debrecen,P.O.Box 400,H-4002 Debrecen,Hungary

出　　处：《Acta Pharmacologica Sinica》2021年第1期36-44,共9页中国药理学报（英文版）

基　　金：This work was supported by the National Natural Science Foundation of China(grant numbers.81703507,81872859,81522045);The research of the Hungarian authors was supported by the EU and cofinanced by the European Regional Development Fund under the project GINOP-2.3.2-15-2016-00008 and the National Research Development and Innovation Office(grant number:K-120181).

摘　　要：Increasing evidence suggests that the use of potent neuroprotective agents featured with novel pharmacological mechanism would offer a promising strategy to delay or prevent the progression of neurodegeneration.Here,we provide the first demonstration that the chiral nonracemic isochroman-2H-chromene conjugate JE-133,a novel synthetic 1,3-disubstituted isochroman derivative,possesses superior neuroprotective effect against oxidative injuries.Pretreatment with JE-133(1–10μM)concentration-dependently prevented H2O2-induced cell death in SH-SY5Y neuroblastoma cells and rat primary cortical neurons.Pretreatment with JE-133 significantly alleviated H2O2-induced apoptotic changes.These protective effects could not be simply attributed to the direct free radical scavenging as JE-133 had moderate activity in reducing DPPH free radical.Further study revealed that pretreatment with JE-133(10μM)significantly decreased the phosphorylation of MAPK pathway proteins,especially ERK and P38,in the neuronal cells.In addition,blocking PI3K/Akt pathway using LY294002 partially counteracted the cell viability-enhancing effect of JE-133.We conclude that JE-133 exerts neuroprotection associated with dual regulative mechanisms and consequently activating cell survival and inhibiting apoptotic changes,which may provide important clues for the development of effective neuroprotective drug lead/candidate.

关 键 词：NEURODEGENERATION oxidative stress apoptosis MAPK pathway PI3K/Akt pathway SH-SY5Y neuroblastoma cells 

分 类 号：R285.5[医药卫生—中药学]